Abstract B018: Suppression of distant metastasis of colorectal cancer by small molecule compound through targeting the oncogenic KITENIN complex
Authors: Sung Jin Kim, Jeong A. Bae, Yoon Gyoon Kim, Eun Ae Kim, Hyung-Ho Ha, Hangun Kim, Kyung Keun Kim
Journal: Cancer Research (2023)

Abstract Distant metastasis is a major reason for cancer-related death. We previously identified KITENIN (KAI1 C-terminal interacting tetraspanin, Vangl1), a gene encoding a membrane-associated protein, as a metastasis-enhancing gene. The oncogenic KITENIN complex is found to be involved in metastatic dissemination of KITENIN-overexpressing colorectal cancer (CRC) cells and also plays an important role in colorectal carcinogenesis within an APC-loss environment, all of which proposing that the KITENIN complex represents a molecular target for therapeutics aimed at blocking the malignant progression of CRC. To develop novel anti-metastatic agents, we sought to identify therapeutics capable of breaking down the oncogenic KITENIN complex in CRC cells and searched for low-molecular weight compounds that break down the complex, thereby shutting off its oncogenic signals. We then tested the effectiveness of the identified substances in suppressing colorectal liver metastasis (CLM). We found a compound that specifically blocked oncogenic signals from the functional KITENIN complex in CRC cells and renamed it as DKC (Disintegrator of KITENIN Complex) compound. DKC compound bound the KH-type splicing regulatory protein (KSRP), a downstream factor and stabilizer of the functional KITENIN complex, and specifically suppressed invasiveness of CRC cells expressing higher levels of KITENIN. After treatment with DKC compound, RACK1 and microRNA-124 were recruited, resulting in removal of KITENIN from the complex followed by its degradation. DKC suppressed hepatic metastasis effectively in a mouse model of CLM with higher KITENIN. Intriguingly, DKC compound combined with 5-fluorouracil resulted in an enhanced therapeutic effect. Thus, disintegration of the functional KITENIN complex following DKC treatment led to alteration of the specific cellular context induced by the KITENIN complex. Among the synthetic DKC analogues, we selected the one as the optimized leading compound. A docking model study suggested that the interaction between the optimized leading compound with KSRP occurs via insertion of the compound into the binding pocket of the fourth KH-domain and pharmacokinectic studies showed that the favorable blood level was maintained after oral or intravenous administration in rat. Overall, DKC compound specifically blocked oncogenic signals from the functional KITENIN complex in CRC cells with higher KITENIN and suppressed CLM by targeting the KITENIN complex. Our results suggest that a combination regimen with DKC compound could be used more effectively to treat distant metastasis and chemoresistance in CRC patients with high KITENIN expression. Citation Format: Sung Jin Kim, Jeong A. Bae, Yoon Gyoon Kim, Eun Ae Kim, Hyung-Ho Ha, Hangun Kim, Kyung Keun Kim. Suppression of distant metastasis of colorectal cancer by small molecule compound through targeting the oncogenic KITENIN complex [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B018.